Abstract Macrophages are central to the pathology in rheumatoid arthritis, driving inflammation in joints of affected patients, but there are currently no therapies available that specifically target macrophages. In this proposal, we seek to characterize hallmark pathways of macrophage dysregulation in arthritis by understanding immunomodulatory receptors that regulate macrophage activation states. In our preliminary data, we have analyzed RNA sequencing on synovial macrophages from a large cohort of patients with arthritis to identify genes that may regulate macrophages in arthritis. Within this dataset, SLAMF7 expression in macrophages was highly associated with disease activity and inflammation. This receptor is expressed by leukocytes and controls their activation through homotypic interactions with SLAMF7 on other cells. A cytoplasmic immunoreceptor tyrosine switch motif (ITSM) can drive either activation or inhibition of cells through this receptor, depending on the cell type and its activation state. However, the role of this receptor on macrophages is not well understood. Based on preliminary data suggesting that activation of this pathway drives inflammatory cytokine secretion, we hypothesize that SLAMF7 drives macrophage activation, amplifying inflammation within the joints of patients with arthritis. This research proposal is focused on understanding how SLAMF7 regulates the activation state of macrophages and to define its contribution to inflammatory arthritis. We will study the role of this receptor on macrophages using human cells (Aim 1) and mouse models of arthritis (Aim 2). We will use in vitro assays to determine how SLAMF7 regulates the activation of macrophages from blood and synovial tissue by quantifying changes in cytokine production, surface activation marker expression, and transcriptomic changes. We will further evaluate the function of this gene in vivo by using mice that are deficient for SLAMF7, in the germline and specifically in macrophages, in models of inflammatory arthritis. We expect that these studies will provide key insights into how SLAMF7 regulates the activation state of synovial macrophages, which may lead to new therapeutic strategies targeting this pathway. In addition to groundbreaking discoveries about how SLAMF7 regulates macrophage function in arthritis, this project will provide the candidate with key skills in computational analyses and mouse models of arthritis that will allow him to progress to become a successful physician scientist leading research to understand the pathways of macrophage dysfunction in arthritis.